MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins.
ABSTRACT MicroRNA have recently been identified as regulators that modulate target gene expression and are involved in shaping the immune response. This study was undertaken to investigate the contribution of microRNA-146a (miR-146a), which was identified in the pilot expression profiling step, to the pathogenesis of systemic lupus erythematosus (SLE).
TaqMan microRNA assays of peripheral blood leukocytes were used for comparison of expression levels of microRNA between SLE patients and controls. Transfection and stimulation of cultured cells were conducted to determine the biologic function of miR-146a. Bioinformatics prediction and validation by reporter gene assay and Western blotting were performed to identify miR-146a targets.
Profiling of 156 miRNA in SLE patients revealed the differential expression of multiple microRNA, including miR-146a, a negative regulator of innate immunity. Further analysis showed that underexpression of miR-146a negatively correlated with clinical disease activity and with interferon (IFN) scores in patients with SLE. Of note, overexpression of miR-146a reduced, while inhibition of endogenous miR-146a increased, the induction of type I IFNs in peripheral blood mononuclear cells (PBMCs). Furthermore, miR-146a directly repressed the transactivation downstream of type I IFN. At the molecular level, miR-146a could target IFN regulatory factor 5 and STAT-1. More importantly, introduction of miR-146a into the patients' PBMCs alleviated the coordinate activation of the type I IFN pathway.
The microRNA miR-146a is a negative regulator of the IFN pathway. Underexpression of miR-146a contributes to alterations in the type I IFN pathway in lupus patients by targeting the key signaling proteins. The findings provide potential novel strategies for therapeutic intervention.
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ABSTRACT: The focus of the present review is on the extent to which epigenetic alterations influence the development of systemic lupus erythematosus. Lupus is a systemic autoimmune disease characterized by the production of autoantibodies directed at nuclear self-antigens. A DNA methylation defect in CD4+ T cells has long been observed in idiopathic and drug-induced lupus. Recent studies utilizing high-throughput technologies have further characterized the nature of the DNA methylation defect in lupus CD4+ T cells. Emerging evidence in the literature is revealing an increasingly interconnected network of epigenetic dysregulation in lupus. Recent reports describe variable expression of a number of regulatory microRNAs in lupus CD4+ T cells, some of which govern the expression of DNA methyltransferase 1. While studies to date have revealed a significant role for epigenetic defects in the pathogenesis of lupus, the causal nature of epigenetic variation in lupus remains elusive. Future longitudinal epigenetic studies in lupus are therefore needed.Arthritis research & therapy 10/2011; 13(5):245. · 4.27 Impact Factor
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ABSTRACT: MicroRNAs are small RNA molecules that regulate gene expression and play critical roles in B cell development and malignancy. miRNA expression is important globally, as B cell specific knockouts of Dicer show profound defects in B cell development; and is also critical at the level of specific miRNAs. In this review, we discuss miRNAs that are involved in normal B cell development in the bone marrow and during B cell activation and terminal differentiation in the periphery. Next, we turn to miRNAs that are dysregulated during diseases of B cells, including malignant diseases and autoimmunity. Further study of miRNAs and their targets will lead to a better understanding of B cell development, and should also lead to the development of novel therapeutic strategies against B cell diseases.Journal of Hematology & Oncology 03/2012; 5:7. · 3.99 Impact Factor
Article: Lack of association of miR-146a and Ets-1 gene polymorphisms with Fuchs uveitis syndrome in Chinese Han patients.[show abstract] [hide abstract]
ABSTRACT: The aim of this study was to investigate the potential association of microRNA-146a (miR-146a) and V-Ets oncogene homolog 1 (Ets-1) gene polymorphisms with Fuchs Uveitis syndrome (FUS). Three single-nucleotide polymorphisms (SNPs), miR-146a/rs2910164, ets-1/rs1128334, and ets-1/rs10893872 were genotyped in 219 Han Chinese patients with FUS and 612 healthy controls using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotype counts were analyzed by the χ² test. No significant difference concerning the genotypic and allelic frequencies of rs2910164, rs1128334, and rs10893872 polymorphisms could be found between patients with FUS and the normal controls. Analysis according to gender did not show any influence of sex on the association of miR-146a and Ets-1 with FUS. Our results suggest that the investigated three SNPs, miR-146a/rs2910164, ets-1/rs1128334, and ets-1/rs10893872, are not associated with FUS in the Han Chinese population.Molecular vision 01/2012; 18:426-30. · 2.20 Impact Factor